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Thrombopoietic activity of tyrosyl-trna synthetase polypeptides

a technology of tyrosyltrna and polypeptides, which is applied in the direction of enzyme stabilisation, peptide/protein ingredients, extracellular fluid disorder, etc., can solve the problems of palliative and non-specific methods, drastic and expensive methods, and previous efforts to utilize thrombopoietin, the primary biological mediator of thrombopoiesis, have failed in the clinic, so as to reduce pulmonary inflammation and pulmonary inflammation.

Active Publication Date: 2014-09-11
ATYR PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The tyrosyl-tRNA synthetase polypeptides effectively stimulate thrombopoiesis, increasing platelet production, and offer a different mechanism of action with potential for higher potency and reduced immune response compared to traditional treatments.

Problems solved by technology

Currently available treatments for thrombocytopenia and related conditions include, for example, corticosteroids, IVIG, splenectomy, and platelet transfusion, which methods are either palliative and non-specific, or drastic and expensive.
In addition, previous efforts to utilize thrombopoietin, the primary biological mediator of thrombopoiesis, have failed in the clinic due to the serious effects observed in patients who developed an immune response to the drug and, consequently, to their own endogenous thrombopoietin.
Thrombopoietin mimetics and small molecule activators of the thrombopoietin receptor are in development but have not been approved by the Food and Drug Administration (FDA).

Method used

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  • Thrombopoietic activity of tyrosyl-trna synthetase polypeptides
  • Thrombopoietic activity of tyrosyl-trna synthetase polypeptides
  • Thrombopoietic activity of tyrosyl-trna synthetase polypeptides

Examples

Experimental program
Comparison scheme
Effect test

example 1

Stimulation of Thrombopoiesis In Vivo

[0252]The effects of a tyrosyl-tRNA synthetase polypeptide on thrombopoiesis were measured in vivo. The tyrosyl-tRNA synthetase polypeptide utilized in the experiments described below is a C-terminal truncation that comprises amino acids 1-364 of the full-length human tyrosyl-tRNA. This C-terminally truncated polypeptide was fused to an eight amino acid C-terminal tag (365-L-E-H-H-H-H-H-H-372) (SEQ ID NO:5). The amino acid sequence of the full-length human tyrosyl-tRNA synthetase is set forth in SEQ ID NO:1.

[0253]To measure the effects of tyrosyl-tRNA synthetase polypeptides on thrombopoiesis, in a first set of experiments, mice were injected subcutaneously twice daily for seven days with 3 μg / kg of the C-terminally truncated tyrosyl-tRNA synthetase polypeptide. In a second set of experiments, mice were injected twice daily for seven days with 1, 3, and 10 μg / kg of the C-terminally truncated tyrosyl-tRNA synthetase polypeptide. In a third set of ...

example 2

In Vitro Measurements of Thrombopoiesis

[0256]Effects on thrombopoiesis may also be measured in vitro. Stem cells are treated in vitro with a tyrosyl-tRNA synthetase polypeptide of the invention to determine its effect on hematopoietic progenitors of the erythroid, myeloid and megakaryocte lineages using colony-forming cell (CFC) assays (e.g., inhibition, stimulation, toxicity, synergism with other cytokines, hematopoietic defects). In addition, CD34+ megakaryocyte progenitor cells are treated in vitro with a tyrosyl-tRNA synthetase polypeptide of the invention to monitor megakaryocyte expansion and differentiation (e.g., increase in number of progenitor cells, stimulation of differentiation, increase in polyploidy). Similar experiments are performed using bone marrow and spleen cells derived from mice treated with a tyrosyl-tRNA synthetase polypeptide.

example 3

Combination Therapy Stimulates Thrombopoiesis

[0257]To assess whether a tyrosyl-tRNA synthetase polypeptide of the present invention has a synergestic and / or additive effect on the proliferation and differentiation of megakaryocytes in vitro, CD34+ cord blood cells are grown in liquid culture medium in the presence of optimal or sub-optimal formulations of cytokines (StemCell Technologies, Vancouver), such as IL-11, and treated with increasing concentrations of a tyrosyl-tRNA synthetase polypeptide. Additivity or synergism can be determined by monitoring the growth and differentiation of the progenitor cells in the two formulation conditions.

[0258]Similarly, in a protocol comparable to that described in Example 1, mice are injected with a limiting amount of thrombopoietin and with increasing amounts of a tyrosyl-tRNA synthetase polypeptide and the effects of the combination therapy on thrombopoiesis in vivo can be determined by platelet and megakaryocyte counts. In addition, combinat...

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Abstract

Thrombopoietic compositions are provided comprising tyrosyl tRNA synthetase polypeptides, including truncations and / or variants thereof. Also provided are methods of using such compositions in the treatment of conditions that benefit from increased thrombopoiesis, such as thrombocytopenia.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a continuation of U.S. application Ser. No. 12 / 482,151, filed Jun. 10, 2009, which claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 61 / 060,747, filed Jun. 11, 2008, each of which is incorporated herein by reference in its entirety.STATEMENT REGARDING SEQUENCE LISTING[0002]The Sequence Listing associated with this application is provided in text format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The name of the text file containing the Sequence Listing is ATYR—009—02US_ST25.txt. The text file is about 38 KB, was created on Feb. 13, 2014, and is being submitted electronically via EFS-Web.BACKGROUND[0003]1. Technical Field[0004]The present invention relates generally to thrombopoietic compositions comprising tyrosyl-tRNA synthetase polypeptides, including truncations and / or variants thereof, and methods of using such compositions in the treat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N9/00C12N9/96
CPCC12N9/96C12N9/93A61K38/53A61P7/00A61P7/04A61P7/06A61P11/00A61P29/00C12Y601/01001Y02A50/30
Inventor BELANI, RAJESHWATKINS, JEFFRY DEANZHANG, WEIVASSEROT, ALAIN PHILLIPPE
Owner ATYR PHARM INC
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